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[11C]PBR28 is a PET radioligand used to estimate densities of the 18 kDa translocator protein (TSPO) in vivo. Since there is no suitable reference region, arterial blood samples are required for full quantification. Here, we evaluate a methodology for full quantification of [11C]PBR28 PET data that does not require either a reference region or blood samples.Simultaneous estimation (SIME) uses time-activity curves from several brain regions to estimate binding potential (BPND), a theoretically more sensitive outcome measure than total distribution volume. SIME can be employed with either a measured arterial input function (AIF) or a template input function (tIF) that has similar shape as the AIF, but with arbitrary amplitude.We evaluated the ability of SIME to detect group differences in TSPO densities using PET and arterial plasma data from 21 Alzheimer's disease (AD) patients and 15 controls that underwent [11C]PBR28 imaging. Regional BPND obtained with tIFs were compared to those obtained using measured AIFs. Standard kinetic modeling was also employed for comparison. The sensitivity of each method to detect group differences in TSPO densities were assessed by comparing estimated effect sizes between AD patients and controls. For this purpose, BPND estimated for one region with high pathological burden (inferior temporal cortex), and for one region with low pathological burden (cerebellum) was used.BPND estimates obtained with SIME and tIFs were close to identical to those obtained with AIF (3.0 ± 21% difference, r2 = 0.78). In this dataset, the effect sizes between AD patients and controls for both SIME with AIF and SIME with tIF were similar (30.3%, p = 0.001 and 31.0%, p = 0.004, respectively) and were each greater than the effect size observed using the two-tissue compartment model (16.1%, p = 0.12). None of the tested methods showed difference in TSPO binding in cerebellum.These results demonstrate that BPND can be estimated for [11C]PBR28 using SIME, and may be useful in clinical studies. In addition, arterial sampling may not be necessary if tIFs can be reliably estimated.